Along with changes in dietary habits, lifestyle, and living environment in recent years, patients with hyperglycemia, obesity, hyperlipidemia, and hypertension, as well as metabolic syndrome including two or more of these risk factors in combination, are increasing in number worldwide, which has become a social problem (Non Patent Literature 1). In any treatment, dietary therapy and exercise therapy are used, and if the effect is low, or the condition is severe, drug therapy is used in combination.
Diabetes is classified into insulin-dependent diabetes mellitus (type 1, IDDM) and non-insulin-dependent diabetes mellitus (type 2, NIDDM), which affects 90% or more of diabetic patients. Insulin injections are used for treatment of IDDM, and sulfonylurea agents, which promote secretion of insulin, thiazolidine dione drugs, which improve insulin resistance, glycosidase inhibitors, which inhibit sugar digestion and absorption, and biguanide drugs, which inhibit gluconeogenesis in the liver, and the like are used for treatment of NIDDM (Non Patent Literature 2). However, none of these drugs necessarily has adequate effects, and an increasing number of patients have serious complications, because efficacy attenuates after long term use.
In the treatment of patients with severe obesity conditions, centrally-acting anorectic agents are used. However, adequate effects have not been achieved due to the limited duration of use and rebound.
Examples of therapeutic agents for hypertension include calcium antagonists, which produce vasodilatation, diuretics, which promote excretion of salts, β blockers, which suppress the sympathetic nerves to reduce heart rate, α blockers, which suppress the sympathetic nerves to produce peripheral vasodilatation, angiotensin converting enzyme inhibitors and angiotensin receptor blockers, which inhibit vasoconstriction by angiotensin, and so forth. However, blood pressure control in early morning, the time of the day when stroke occurs most commonly, is difficult, and antihypertensive therapies are far from being adequate at present.
As therapeutic agents for hyperlipidemia, HMG-CoA reducing enzyme inhibitors, which inhibit cholesterol synthesis in the liver, fibrate drugs, which inhibit triglyceride synthesis in the liver, anion exchange resins, which promote excretion of bile acid, and the like are used. The ultimate aim of hyperlipidemia treatment is prevention of atherosclerotic diseases including coronary artery diseases and cerebral infarction. However, since the condition of atherosclerosis is caused not only by hyperlipidemia but also coexisting risk factors such as hypertension, diabetes, adiposity, and aging, it is critical to pay attention to such other risk factors all the time, and multidimensional approaches are required (Non Patent Literature 3).
Carbohydrate corticoid (cortisol in humans, corticosterone in rodents) is known to have various bioactivities for regulating blood sugar levels, blood pressure, and the like. For example, it is known that carbohydrate corticoid has a bioactivity of promoting the release of amino acids from muscles and the release of fatty acids and glycerol from adipose tissues into the blood via expression of various proteins to promote gluconeogenesis in the liver using these substrates, leading to the promotion of increased blood sugar levels. Furthermore, it is also known that carbohydrate corticoid has activities of maturing immature fat cells in adipose tissues, leading to adiposity, and acting on mineral corticoid receptors in the kidneys to elevate blood pressure. Mechanisms for regulating carbohydrate corticoid activity involve regulation of production and secretion of carbohydrate corticoid in the hypothalamus-pituitary gland-adrenal cortex route and recycling of carbohydrate corticoid by 11β-HSD1 (conversion from an inactive form to an active form) in target organs such as the liver, adipose tissues, and the lungs (Non Patent Literature 4). The 11β-HSD1 inhibitors are expected to prevent hyperglycemia, adiposity, hyperlipidemia, and/or hypertension by inhibiting carbohydrate corticoid actions in these tissues and to exhibit multidimensional effects on metabolic syndrome including these conditions in combination. These potentials are supported by reports of adiposity with visceral fat, aggravation of glucose tolerance impairment, insulin resistance, and elevated blood pressure in mice with highly expressed adipose tissue-specific 11β-HSD1 (Non Patent Literature 5 and Non Patent Literature 6). The term “metabolic syndrome” means a combination of symptoms associated with abnormal metabolic functions for carbohydrates and lipids in the organism. The diagnosis criteria for this syndrome vary with a number of international organizations, but are consistent in having two or more symptoms among glucose tolerance impairment (or insulin resistance), adiposity, hypertension, hypertriglyceridemia, and low HDL cholesterol levels in blood. These symptoms are described in detail in Non Patent Literature 7. Examples of other expected effects of the 11β-HSD1 inhibitors include effects on atherosclerosis (Non Patent Literature 8), dementia (Non Patent Literature 9), osteoporosis (Non Patent Literature 10), and glaucoma (Non Patent Literature 11).
As a compound having the effect of inhibiting 11β-HSD1, a compound in which a triazole ring bound with a biaryl group and a tetrahydrothiazepine ring are condensed is described in Patent Literature 1. Furthermore, a compound in which a triazole ring bound with a cycloalkyl group and a diazepine ring are condensed is described in Patent Literature 2. Furthermore, a compound in which a condensed ring of a triazole ring and a pyridine ring and a biaryl group each bind to the same carbon atom in a cycloalkyl group is described in Patent Literature 3.